- Journal of Allergy and Clinical Immunology

Anaphylaxis during anesthesia in France: An 8-year national
survey
chot, PharmD,c Yves Auroy, MD, PhD,d
Paul Michel Mertes, MD, PhD,a François Alla, MD, PhD,b Philippe Tre
e
actions Anaphylacto€ıdes Peranesthe
siques* Nancy and Le Vesinet,
Eric Jougla, PhD, and the Groupe d’Etudes des Re
France
Background: More attention should be paid to rare serious
adverse events such as anaphylaxis to increase the safety of
anesthesia.
Objective: To report the results of an 8-year survey of
anaphylaxis during anesthesia in France.
Methods: Data from patients who experienced anaphylaxis
between January 1, 1997, and December 31, 2004, were
analyzed. Estimated incidences were obtained by combining
this database with data from the French pharmacovigilance
system by using a capture-recapture method. The number of
From aService d’Anesthesie Reanimation Chirurgicale, H^opital Central, CHU de Nancy,
INSERM U 911 – Groupe Choc; bService d’epidemiologie, CIC-EC INSERM,
H^opital Central, Centre Hospitalier Universitaire de Nancy; cCentre de Pharmacovigilance de Nancy, H^
opital Central, CHU de Nancy, and dService d’Anesthesie
Reanimation, H^
opital d’Instruction des Armees Val de Gr^ace; and eCepiDc, INSERM,
National Institute for Health and Medical Research, Le Vesinet.
*Groupe d’Etudes des Reactions Anaphylacto€ıdes Peranesthesiques: Angers: C. Cottineau, MD, M. Drouet, MD. Besançon: P. Girardin, MD, P. Koeberle, MD, M. Vigan,
MD. Bordeaux - Pellegrin Tripode: S. Guez, MD, P. Maurette, MD, PhD. Brest: J. C.
Rakotoseheno, MD. Caen: D. Laroche, MD, M. C. Vergnaud, MD. Ch^alons-sur-Sa^one:
P. Scherer, MD. Cherbourg: D. Herbin, MD. Clermont-Ferrand: O. Outtas, MD. Colmar: O. Theissen-Laval, MD. Dieppe: B. Deschamps, MD. Dijon: E. Collet, MD, N.
Louvier, MD, S. Seltzer, MD. Dreux: B. Duffin, MD. Epinal: E. Beaudoin, MD.
Grasse: P. Dugue, MD. Grenoble: M. Honarmand-Pepin, MD, C. Jacquot, MD. Lille
Institut Catholique: C. Castelain-Hacquet, MD. Le Kremlin-Bic^etre: C. Fessenmeyer,
MD. Lille CHU: A. Facon, MD. Limoges: I. Orsel, MD, J. Sainte-Laudy, MD. Lorient:
C. Bernard, MD. Lyon: Y. Beno^ıt, MD, N. Diot-Junique, MD, J. Dubost, MD, R. Dubost, MD, L. Guilloux, MD, I. Topenot, MD. Marseille: J. Birnbaum, MD, D. Vervlo€et,
MD, PhD. Montpellier: P. Demoly, MD, PhD, M. C. Bonnet-Boyer, MD. Nancy: I.
Gastin, MD, J. L. Gueant, MD, PhD, M. C. Laxenaire, MD, PhD, P. M. Mertes,
MD, PhD, G. Kanny, MD, PhD, D. A. Moneret-Vautrin, MD, PhD, C. Mouton, MD.
Nantes: S. Decagny, MD, M. Pinaud, MD, F. Wessel, MD. Narbonne: C. Gallen,
MD. Nice: E. Aguinet, MD, S. Leroy, MD, G. Occelli, MD. N^ımes: M. Joncourt,
MD. Orleans: J. P. Delalande, MD, B. Lemaire, MD, W. S. Mfam, MD. Paris Bichat:
S. Chollet-Martin, MD, PhD, C. Neukirch, MD, P. Nicaise-Roland, MD, C. SauvanPistof, MD. Paris-Pitie: A. M. Korinek, MD. Paris-Necker: C. Karila, MD. ParisPasteur: M. T. Guinnepain, MD. Paris-Creteil: M. Bellanger, MD. Paris-Roosevelt:
M. Dona, MD, A. Seringulian, MD. Paris-Saint-Joseph: M. L. Megret-Gabeaud,
MD. Paris-Tenon: N. Abuaf, MD, H. Gaouar, MD, J. E. Antegarden, MD, F. Leynadier,
MD, PhD. Poitiers: K. Breuil, MD, L. Grandon, MD. Reims: A. Gallet-Browaeys, MD,
F. Lavaud, MD, J. M. Malinovsky, MD, PhD. Rennes: Y. Delaval, MD, M. M. Lucas,
MD, C. Rochefort-Morel, MD. Rouen: Y. Meunier, MD, D. Provost, MD. SaintEtienne: C. Dzviga, MD, M. Mangin, MD. Saint-Nazaire: J. P. Mallet, MD. Strasbourg: R. Stenger, MD, S. Le Borgne, MD, J. Valfrey, MD. Tarbes: J. Gayraud, MD.
Toulouse-Larrey: A. Didier, MD, PhD, D. Giamarchi, MD. Toulouse-Rangueil: I. Migueres, MD. Tours: P. Carre, MD.
Disclosure of potential conflict of interest: The authors have declared that they have no
conflict of interest.
Received for publication August 11, 2010; revised February 19, 2011; accepted for publication March 2, 2011.
Available online April 17, 2011.
Reprint requests: Paul Michel Mertes, MD, PhD, Service d’Anesthesie-Reanimation,
CHU de Nancy, H^
opital Central, 29 Avenue de Lattre de Tassigny, 54035 Nancy
Cedex, France. E-mail: [email protected].
0091-6749/$36.00
Ó 2011 American Academy of Allergy, Asthma & Immunology
doi:10.1016/j.jaci.2011.03.003
366
patients exposed to the offending agents was obtained from
data collected during the national survey of anesthesia
practice.
Results: A total of 2516 patients was included. A diagnosis of
IgE-mediated reaction was established in 1816 cases (72.18%).
The most common causes were neuromuscular blocking agents
([NMBAs]; n 5 1067; 58.08%), latex (n 5 361; 19.65%), and
antibiotics (n 5 236; 12.85%). The median annual incidence
per million procedures was higher for females 154.9 (5th-95th
percentile, 117.2-193.1) than for males 55.4 (5th-95th
percentile, 42.0-68.0). It reached 250.9 (5th-95th percentile,
189.8-312.9) for women in cases of allergic reactions to NMBAs.
In children, a diagnosis of IgE-mediated reactions was obtained
in 122 cases (45.9%). The most common causes were latex
(n 5 51; 41.8%), NMBAs (n 5 39; 31.97%), and antibiotics
(n 5 11; 9.02%). In contrast with adults, no female
predominance was observed.
Conclusion: The incidence of allergic reactions during
anesthesia, estimated on a national basis, is higher than
previously estimated. These results should be taken into account
in the evaluation of the benefit-to-risk ratio of the various
anesthetic techniques in individuals. The similar incidence of
reactions according to sex before adolescence suggests a role for
sex hormones in the increase of anaphylaxis observed in women.
(J Allergy Clin Immunol 2011;128:366-73.)
Key words: Anaphylaxis, anesthesia, epidemiology, sex, children,
neuromuscular blocking agents, latex, antibiotics
The safety of anesthesia has been significantly improved during
the last decades.1 However, it may still be considered risky because
it results from the exposure of a patient to a mixture of drugs that
deliberately alter physiological functions in a short space of time.
Complications frequently have multiple causes resulting from systems failure or from patients’ underlying conditions.2,3 To improve
patient safety further, one should focus on education and guidelines, which should include the prevention, diagnosis, and treatment of rare but serious events that may occur during anesthesia.
Adverse drug reactions have been recognized as one of the most
common causes of death in medical practice.4,5 Therefore, increasing attention has been paid over these last decades to allergic reactions that may occur during the very vulnerable perioperative
period. However, despite systematic efforts aimed at characterizing
the epidemiology of these reactions, it remains poorly defined. Indeed, the surveillance and analysis of adverse drug reactions represent a statistical challenge because these reactions are rare,
random, and mostly independent from the successive exposure of
patients to a low-risk intervention. Reporting processes range
from spontaneous to statutory systems. However, because of possible biases and underreporting, these reporting systems are usually
J ALLERGY CLIN IMMUNOL
VOLUME 128, NUMBER 2
Abbreviations used
GERAP: Groupe d’Etudes des Reactions Anaphylactiques
Peranesthesiques
HIS: Immediate hypersensitivity reaction
HSI-IgE: Immediate hypersensitivity reaction-IgE-mediated
HSI–non-IgE: Immediate hypersensitivity reaction not mediated by
IgE
NMBA: Neuromuscular blocking agent
considered inappropriate for the assessment of adverse drug
reaction rates or differences in incidence rates.6-8 Nevertheless,
when independent sources are available, the capture-recapture
method, based on the intersection of the 2 data sources with the
aim of identifying the number of common cases, can be used to
estimate the number of unreported cases.9-11
In this report, data were collected by Groupe d’Etudes des
Reactions Anaphylactiques Peranesthesiques (GERAP), a spontaneous reporting system that performs studies concerning hypersensitivity reactions occurring during anesthesia since 1985.12-18
This was used to provide a complete description of the clinical
symptoms, risk factors, and substances responsible for the reactions, with a special emphasis on the respective characteristics
of reactions occurring in adults and children. The database was
combined with data from the French drug surveillance
system19—that is, the national official reporting system of adverse
drug reactions—to estimate the real number of allergic reactions
by using the capture-recapture method. Finally, the incidence
rates of allergic reactions were estimated by using the number
(denominator) and characteristics of the populations exposed to
the various drugs responsible for the hypersensitivity reactions
collected during the French survey of anesthesia, as conducted
by the French Society of Anesthesia and Intensive Care.20
METHODS
Study design
Data from patients who experienced an immediate hypersensitivity reaction (HSI) during anesthesia suspected of being allergic in origin were
prospectively included in the GERAP national register. The mechanism of the
reaction (immediate hypersensitivity reaction-IgE-mediated [HSI-IgE] or
nonimmunologic or immunologic other than immediate hypersensitivity
reaction not mediated by IgE [HSI–non-IgE]) was assessed on the basis of a
standardized diagnostic protocol performed in allergo-anesthesia outpatient
clinics by members of the GERAP network.21 The number of IgE-mediated
reactions to hypnotics, opioids, neuromuscular blocking agents, and other
agents was first described as a direct indication of the contribution of the various agents involved.
An additional analysis was then performed in an attempt to refine the
incidence of anaphylaxis during anesthesia over the last 2-year period studied
(2003-2004), using information provided by 2 additional databases. A specific
analysis of hypersensitivity reactions during anesthesia, combining results from
the GERAP database with results from the French Pharmacovigilance System
database by using a capture-recapture method, was performed.10,11 Estimates
of the annual incidence of anesthesia and of the drugs used in the anesthetic
protocols were obtained from the database of the French national survey of anesthesia conducted in 1996 by the French Society of Anesthesiology in close
collaboration with Institut National de la Sante et de la Recherche Medicale.20
Data and assessments
GERAP. Cases recorded between January 1, 1997, and December 31,
2004, were included in the study. An intermediate analysis of part of the
MERTES ET AL 367
clinical cases reported here has been included in previous reports on a series of
3 consecutive 2-year surveys.12,17,18 These previous cases are pooled with new
results from our last 2-year survey (January 1, 2003, to December 31, 2004) to
conduct a large database analysis. This allows us to compare results in children
and adults for the first time.
Investigations were performed according to standardized procedures as
recommended by the French Society of Anesthesiology and the French
Society of Allergology.21 The diagnostic protocol included a standardized
questionnaire. Reactions were graded from I to IV depending on increasing severity (grade I, presence of cutaneous signs; grade II, presence of measurable
but not life-threatening symptoms, including cutaneous effects, arterial hypotension, cough, or difficulty in mechanical ventilation; grade III, presence of
life-threatening reactions: cardiovascular collapse, tachycardia or bradycardia, arrhythmias, severe bronchospasm; grade IV, circulatory inefficacy, cardiac and/or respiratory arrest).
Data concerning allergy investigations were systematically recorded: type
of skin tests performed (ie, skin prick test and/or intradermal test), dilution of
the tested drug leading to a positive reaction, and cross-reactivity between
neuromuscular blocking agents (NMBAs) in cases of adverse reaction to a
NMBA.22,23 Also recorded were the results of plasma histamine (RIA Histamine; Immunotech, Marseille, France) and serum tryptase monitoring (UniCAP Tryptase; Phadia SAS, Saint Quentin en Yvelines, France) during the
adverse reaction, and of IgE-specific assays testing responses to quaternary
ammonium (quaternary ammonium sepharose radioimmunoassay or P-aminophenylphosphoryl-choline radioimmunoassay),24,25 latex, or antibiotics
(Cap System; Phadia SAS) when available. Values above 9 nmol L-1 for histamine and 25 mg L-1 for tryptase were considered positive.
Pathogenic mechanisms were defined in accordance with the nomenclature
proposed by the European Academy of Allergy and Clinical Immunology and
the World Allergy Organization.26,27 IgE-mediated reactions (HSI-IgE) were
diagnosed on the basis of skin test and/or IgE assay results consistent with the
clinical history of the adverse reaction and the anesthetic protocol. Otherwise,
the diagnosis of non-IgE–mediated reaction (HSI–non-IgE) was retained.
French Pharmacovigilance System. The French Pharmacovigilance System is the official national self-reporting system of adverse drug
reactions based on a network of 31 regional centers that receive spontaneous
adverse drug reaction reports from health professionals. After any declaration,
a specific enquiry is conducted by a specialist, and a final diagnosis based on a
causality assessment is established by applying the criteria of Moore et al,28
which combine chronologic and semiologic criteria. A query in this database
was performed on January 24, 2007, with the following terms: ‘‘anaphylactic
reaction,’’ ‘‘anaphylactoid reaction,’’ and ‘‘anaphylactic shock.’’ A total of 773
cases were identified in the period 2003 to 2004, and 159 cases related to anesthesia were considered eligible.
French national survey of anesthesia. The annual number
of anesthesias performed in France in 1996, as well as the 95% CI, has been
estimated in a national survey.20 This study, initiated by the French Society of
Anesthesia and Intensive Care, collected information that included the characteristics of patients (age, sex, American Society of Anesthesiologists status),
the techniques of anesthesia, and the nature of the procedure for which anesthesia was required. All French private, public, and military hospitals were
asked to participate in this survey. All anesthetic procedures were documented
and collected over 3 consecutive days chosen at random during a 12-month period to obtain a representative sample of the annual activity. The participation
rate of hospitals was 98%, and 62,415 questionnaires were collected, corresponding to 7,756,121 anesthetic procedures performed in France in 1996.
For our incidence analysis, we had full access to data from this survey.
Causal drugs and incidence estimates. The number of IgEmediated reactions to the responsible agents was initially established by using
the GERAP database. These results were merged with data from our 2
additional databases. To assess the incidence of anaphylactic reactions during
anesthesia, we estimated (1) the annual number of anaphylactic reactions
related to anesthesia, and (2) the annual number of anesthetics performed in
France within the 2003 to 2004 period.
Estimation 1: Annual number of anaphylactic reactions related to anesthesia. The annual number of anaphylactic
368 MERTES ET AL
reactions related to anesthesia was obtained by a capture-recapture
method10,11 using the 2 independent sources described: the GERAP network
database and the French Pharmacovigilance System database. We adopted the
following inclusion criteria for both sources: IgE-mediated reaction related to
anesthesia, reaction occurring in the years 2003 to 2004, and reaction occurring in a geographic area covered by both sources (63% of French population).
Patients with identical geographic location, sex, and age (63 years) were
considered potential overlaps. Each of these cases was manually checked to
identify overlapping patients. After identifying the overlaps, log-linear models
for the capture-recapture method were used to estimate the total number of anaphylaxis episodes in the study area, as well as the 95% CI. An extrapolation
including a sex and age standardization provided the total number of annual
episodes of anaphylaxis in France.
Estimation 2: Annual number of anesthesias performed in France. The annual number of anesthesias performed in
France in 1996 and the 95% CI have been estimated previously in a national
survey.20 For our incidence analysis, we had full access to data from this
survey. As a result of extrapolating the evolution of annual procedures provided by medico-administrative data, and the stability of the number of vials
of neuromuscular blocking agents used in France—5,879,000 from 1997 to
1998, 6,157,000 from 1999 to 2000, 5,721,000 from 2001 to 2002, and
6,081,000 from 2003 to 200429—we consider that the number of anesthetic
procedure remained stable in France during the period 1996 to 2004.
Estimation of the incidence of anaphylaxis during
anesthesia. The incidence of anaphylaxis during anesthesia was estimated by combining estimations (1) and (2) in the following formula:
Incidence 5 annual number of anaphylactic reactions related to anesthesia=
annual number of anesthesias performed in France:
Incidences were calculated for all patients according to sex, age class (/5
years), and the more frequently involved causal drug present in both sources
(opioids, neuromuscular blocking agents, hypnotics). Allergic reactions to latex are not reported to the national pharmacovigilance system, and information concerning the use of antibiotics during anesthesia was not recorded in
the survey of anesthesiology practice in France. Therefore, the methods providing estimates of incidences of allergic reactions to latex and antibiotics
could not be used. With this limitation in mind, incidences were estimated
by taking into account the proportion of allergic reactions identified by the
GERAP network. It was assumed that all patients had potentially been
exposed to latex and that the incidence for antibiotics was derived from the estimated incidence of allergic reactions and the relative contribution of antibiotics in the GERAP database.
The 95% CIs of estimated incidences were evaluated by the Monte Carlo
simulation technique.30 This method consists of randomly generating a high
number (ie, 10,000) of ratios (the number of cases/the number of exposures)
and calculating the median and 5th to 95th percentile intervals of the distribution of obtained ratios. The numerators and the denominators of ratios were
generated from Poisson distributions with the observed number of cases and
the number of exposed persons, respectively, as mean values.
Statistical analysis was performed by using the SAS 8.02 software (SAS
Institute Inc, Cary, NC). Values were expressed as mean 6 SD or percentages.
Intergroup comparisons used ad hoc methods (Pearson x2 test, Mann-Whitney
_.05 was considered statistically
test, ANOVA, or correlation). A P value <
significant.
RESULTS
GERAP database
A total of 2516 patients were included. At the end of the allergy
workup, a diagnosis of IgE-mediated immediate hypersensitivity
reaction was established in 1816 cases (72.18%), whereas the
remaining 700 cases (27.82%) were considered non–IgE-mediated hypersensitivity reactions. The rate of hypersensitivity
reactions and the distribution according to the mechanism of
hypersensitivity remained stable throughout the entire study
period.
J ALLERGY CLIN IMMUNOL
AUGUST 2011
TABLE I. Agents involved in IgE-mediated reactions during
anesthesia (1816 patients, 1851 substances) between January 1,
1997, and December 31, 2004
Causal agent
NMBAs
Succinylcholine
Rocuronium
Atracurium
Vecuronium
Pancuronium
Mivacurium
Cisatracurium
Total
Latex
Antibiotics
Penicillin
Cephalosporin
Others
Total
Hypnotics
Propofol
Midazolam
Pentothal
Ketamine
Total
Opioids
Morphine
Fentanyl
Sufentanil
Nalbuphine
Remifentanil
Total
Colloids
Gelatin
Hetastarch
Albumin
Total
Local anesthetics
Bupivacaine
Lidocaine
Mepivacaine
Total
Other agents
Patent blue
Methylene blue
Propacetamol
Aprotinin
Protamine
Nonsteroidal anti-inflammatory drugs
Papain
Nefopam
Ethylene oxide
Steroids
Hyaluronidase
Metabisulfite
Povidone
Contrast media
Total
Reactions (%)
No. of patients
58.08
33.40
29.30
19.30
10.20
3.60
2.50
1.70
100
19.65
12.85
49
37
14
100
2.34
55.80
32.60
9.30
2.30
100
1.69
35.5
22.6
22.6
12.9
6.5
100
3.43
88.9
9.5
1.6
100
0.33
50.0
33.3
16.7
100
2.40
25.0
2.3
20.5
11.4
9.1
6.8
6.8
4.5
2.3
2.3
2.3
2.3
2.3
2.3
100
1067
356
313
206
109
38
27
18
361
236
115
88
33
43
24
14
4
1
31
11
7
7
4
2
63
56
6
1
6
3
2
1
44
11
1
9
5
4
3
3
2
1
1
1
1
1
1
The most common causes of anaphylactic reactions were NMBAs
(n 5 1067; 58.08%), followed by latex (n 5 361; 19.65%) and
antibiotics (n 5 236; 12.85%; Table I). Succinylcholine (n 5 356;
33.4%) was most frequently incriminated, followed by rocuronium
(n 5 313; 29.3%), atracurium (n 5 206; 19.3%), and vecuronium
MERTES ET AL 369
J ALLERGY CLIN IMMUNOL
VOLUME 128, NUMBER 2
TABLE II. Estimated annual incidence of IgE-mediated allergic reactions during anesthesia
Estimated annual incidence (/million)
Median (5th-95th percentile)
Causal agent
Overall
Neuromuscular blocking agents
Latex
Antibioticsà
Other agentsà
Estimated annual no. of cases
780
458
155
101
80
(555-1005)
(326-590)
(110-200)*
(72-131)
(57-103)
Male
Overall
Female
55.4 (42.0-69.0)
105.5 (79.7-132.0)
32.6 (24.7-40.5)
—
—
100.6 (76.2-125.3)
184.0 (139.3-229.7)
59.1 (44.8-73.6) —
—
154.9 (117.2-193.1)
250.9 (189.8-312.9)
91.0 (68.9-113.4)
—
—
*Extrapolation based on cases identified in the GERAP database.
All patients were considered to be exposed to latex during the perioperative procedure.
àNumber of patients exposed not recorded in the survey of anesthesia practice.
(n 5 109; 10.2%), whereas reactions to other nondepolarizing
NMBAs were less common. Reactions involving latex initially increased to reach a plateau from 2000 to 2004. Reactions involving
antibiotics, after a rapid increase, remained stable from 1998 to
2004. Hypnotics, opioids, and local anesthetics were rarely involved.
Colloids were incriminated in 63 cases, and other substances in 44
cases, with an unexpectedly high number of reactions involving
dyes from 2002 to 2004.
Estimation of the incidence of allergic reactions
during anesthesia
During the period from 2003 to 2004, the pharmacovigilance
network registered 159 eligible cases and the GERAP network
281. Among the 91 potential overlap cases, 30 were identified as
real overlaps. From this data, the calculation provided an annual
number of 625 (5th-95th percentile, 445-805) cases in France. This
annual number can be extrapolated to 780 (5th-95th percentile,
555-1005) when cases involving latex, which are recorded only in
the GERAP database, are included (Table II). The completeness of
registration was 17.1% for pharmacovigilance and 22.2% for the
GERAP network. Given the 7,756,121 (5th-95th percentile,
7,374,848-8,137,394) anesthetic procedures performed annually
in France and the 780 (5th-95th percentile, 555-1005) IgEmediated reactions related to these procedure, the estimated
median annual incidence was 100.6 (5th-95th percentile, 76.2125.3) per million procedures. This incidence was higher for females (5th-95th percentile, 154.9 [117.2-193.1]) than males
(5th-95th percentile, 55.4 [42.0-68.0]). It reached a maximum of
250.9 (5th-95th percentile, 189.8-312.9) for women and 105.5
(5th-95th percentile, 79.7-132.0) for men when allergic reactions
to NMBAs had occurred. Estimations of the incidence according
to sex and age class (/5 years) are presented in Fig 1.
Associated factors
Results regarding associated factors are described according to
information collected in the GERAP database. A history of
previous anesthesia was not a risk factor for immediate hypersensitivity reaction except in patients with a history of adverse
reaction during a previous anesthesia. No difference was observed
between IgE and non–IgE-mediated reactions when the incidences of atopy (16.32% vs 17.47%; P 5 nonsignificant), asthma
(9.90% vs 8.30%; P 5 nonsignificant), or drug intolerance were
compared (18.54% vs 16.10%; P 5 nonsignificant). A history
of food intolerance was more frequently reported in case of
IgE-mediated reactions (8.49 vs 3.64; P < .0001; Table III).
This difference was related to a higher proportion of atopic patients who were sensitized to latex. Allergy to latex was
FIG 1. Estimated incidence of IgE-mediated allergic reactions according to
sex and age ranges (5 years).
significantly associated with a history of atopy, asthma, or food
intolerance (P < .0001). Moreover, in 176 of 361 patients
(48.6%) who experienced an IgE-mediated reaction to latex, careful retrospective assessment of their medical history revealed the
presence of symptoms suggestive of latex sensitization such as
fruit allergy or intolerance to materials containing rubber latex before the reaction. Allergy to antibiotics was associated with a positive history of drug intolerance (P < .01), whereas no significant
risk factors could be identified regarding allergy to NMBAs. Anaphylaxis to an NMBA was observed in 131 patients (12.6%) who
had no history of anesthesia before the current adverse reaction,
and therefore no previous exposure to any NMBA.
Clinical features
Clinical features are described according to information
collected in the GERAP database. IgE-mediated and non–IgEmediated immediate hypersensitivity reactions cannot be distinguished on the basis of clinical symptoms alone. However,
clinical manifestations were more severe in patients with
documented IgE-mediated than in patients presenting with a
non–IgE-mediated reaction (P < .0001; Fig 2, A). Most IgEmediated reactions were grade 3 (n 5 1092; 60.132%), whereas
non–IgE-mediated reactions were mainly grade 1 (n 5 372;
53.143%).
370 MERTES ET AL
J ALLERGY CLIN IMMUNOL
AUGUST 2011
TABLE III. Clinical symptoms, tryptase levels, and history of
allergies according to mechanism of immediate hypersensitivity
reactions during anesthesia in the general population between
January 1, 1987, and December 31, 2004 in France
Clinical symptoms
Cutaneous symptoms
Erythema
Urticaria
Angioedema
Cardiovascular symptoms
Hypotension
Cardiovascular collapse
Cardiac arrest
Bronchospasm
Median tryptase mg L-1
Median (range)
Atopy
Asthma
Drug intolerance
Food intolerance
HSI-IgE (%)
HSI–non-IgE (%)
70.24
47.27
20.31
11.08
84.04
21.861
54.901
5.34 (n 5 97)
41.35
45
(1-1020)
16.32
9.90
18.54
8.49
95.34
68.41
25.62
8.30
36.39
20.14
10.57
0.29 (n 5 2)
19.29
6
(1-106)
17.47
8.0
16.10
3.64
FIG 2. Frequencies of clinical severity grade of IgE-mediated and non–IgEmediated hypersensitivity reactions between January 1, 1997, and December 31, 2004, in France in the general population (A) and in children (B).
The various clinical features observed during IgE-mediated
and non–IgE-mediated immediate hypersensitivity reactions are
summarized in Table III. Cutaneous symptoms were absent in one
third of IgE-mediated reactions (non–IgE-mediated 95.34% vs
70.24% IgE-mediated reactions; P <.0001), whereas angioedema
was more frequently observed in IgE-mediated reactions. Cardiovascular symptoms (84.04% vs 36.39%; P < .0001) were more
frequent in cases of IgE-mediated reactions, with a higher frequency of cardiovascular collapse (non–IgE-mediated 10.571%
vs 54.901% IgE-mediated reactions; P < .0001). Cardiac arrest
was noticed in 97 cases of IgE-mediated reactions. Bronchospasm, another symptom classically associated with a higher reaction severity (grade 3 or 4), was also more frequent in the
case of IgE-mediated reactions (non–IgE-mediated 19.286% vs
41.355% IgE-mediated reactions; P < .0001).
Clinical symptoms may also occur as an isolated phenomenon.
In HIS-IgE reactions, cardiovascular collapse was the sole feature
in 164 cases, hypotension in 32 cases, cardiac arrest in 45 cases,
bronchospasm in 26 cases, and cutaneous symptoms in 53 cases.
Angioedema never occurred alone. Cutaneous symptoms were
the sole feature in 375 non–IgE-mediated reactions.
Tryptase levels were significantly elevated (>25 mg L-1) in 68%
of IgE-mediated reactions (median, 45 mg L-1; range, 1-1020),
whereas an increased level was observed in 4% of non–IgE-mediated reactions (median, 6 mg L-1; range, 1-106; Table III).
FIG 3. Distribution of IgE-mediated and non–IgE-mediated hypersensitivity
reactions in children according to age ranges (years) between January 1,
1997, and December 31, 2004, in France for latex and NMBAs (A) and for IgE
and non–IgE-mediated reactions (B).
Features particular to children
A subgroup analysis was conducted in children under the age of
18 years. A total of 266 children were included. A diagnosis of
IgE-mediated reaction was made in 122 cases (45.9%). The
distribution according to age and mechanism of the reaction is
displayed in Fig 3, A.
The various incriminated substances differ significantly from
those for adult patients. Latex was the most frequently incriminated substance (n 5 51 cases; 41.8%), followed by NMBAs
(n 5 39; 31.97%) and antibiotics (n 5 11 cases; 9.02%). The
distribution of sensitization according to age was significantly
different for these substances. Sensitization to latex was diagnosed as of 2 years of age, and its distribution was quite
homogenous in children, whereas the number sensitized to
NMBAs or antibiotics became more frequent in adolescents
(Fig 3, B).
In contrast with the results observed in adults, no significant
differences were observed in regard to the sex distribution in
children for both mechanisms (IgE-mediated reactions: male, n 5
61 cases [50%], female, n 5 61 cases [50%]; non–IgE-mediated
reactions: male, n 5 78 cases [55.2%], female, n 5 66 cases
[45.8%]).
As reported in adults, no differences were observed between
IgE-mediated and non–IgE-mediated reactions when the incidences of atopy (31.15% vs 23.60%; P 5 nonsignificant), asthma
(14.75% vs 11.81%; P 5 nonsignificant), or drug intolerance
MERTES ET AL 371
J ALLERGY CLIN IMMUNOL
VOLUME 128, NUMBER 2
TABLE IV. Clinical symptoms and history of allergies according
to mechanism of immediate hypersensitivity reactions during
anesthesia in children between January 1, 1997, and December
31, 2004 in France
Cutaneous symptoms
Cardiovascular symptoms
Bronchospasm
Atopy
Asthma
Drug intolerance
Food intolerance
HIS-IgE (%)
HSI–non-IgE (%)
83.6
42.62
42.62
31.15
14.75
15.58
13.93
97.9
20.83
15.28
23.6
11.81
20.14
4.17
were compared (15.58% vs 20.14%; P 5 nonsignificant). However, once again, a history of food intolerance was more frequently reported in the case of IgE-mediated reactions (13.93
vs 4.17; P <.01; Table IV). This difference was related to a higher
proportion of atopic patients who were sensitized to latex. In addition, atopy (31.15% vs 16.32%; P < .0003) and a history of food
intolerance (13.93% vs 8.49%; P < .004) were more frequent in
children with an IgE-mediated hypersensitivity reaction compared with adults.
Clinical manifestations were more severe in IgE-mediated than
in non–IgE-mediated reactions (P < .0001). Most IgE-mediated
reactions were grade 3 (n 5 50; 40.98%), whereas non–IgEmediated reactions were mainly grade 1 (n 5 100; 69.44%).
The various clinical features observed during IgE-mediated
and non–IgE-mediated immediate hypersensitivity reactions are
summarized in Table IV. Cardiovascular symptoms were more
frequent in cases of IgE-mediated reactions than in non–IgEmediated reactions (P < .0002), but this difference was less
pronounced than in adults. Only 1 episode of circulatory collapse
was reported, and it occurred in a 5-year-old girl sensitized to
atracurium. Bronchospasm was also more frequent in case of
IgE-mediated reactions (P < .0001).
DISCUSSION
This combined analysis of 3 different databases allows us to
provide a nationally based estimate of the incidence of immediate IgE-mediated allergic reactions occurring during anesthesia, according to sex, age, and causal substance. To our
knowledge, this report represents the first attempt to provide an
accurate estimate of the frequency of allergic reactions using the
capture-recapture method and the largest cohort of patients
available in the literature. It confirms the general view that
immediate-type hypersensitivity reactions are largely underreported, with a higher incidence (100.6 [76.2-125.3] per million
procedures) of allergic reactions than previously reported,14,31
with women at significantly higher risk than men. In addition,
this study highlights for the first time the specificities of allergic
reactions in children. The similar incidence of allergic and nonallergic reactions according to sex before adolescence strongly
suggests a role for sex hormones in the increase of immediate hypersensitivity reactions observed in women. These results should
be taken into account when evaluating the benefit-to-risk ratio of
the different anesthesia techniques in the different subsets of the
population.
The leading causes of allergic reactions in France are NMBAs,
followed by latex and antibiotics used for antimicrobial prophylaxis. These results call for an active policy of risk reduction,
combining a reduction of unnecessary exposure to potentially
sensitizing compounds and a systematic search for possible risk
factors before anesthesia. The wide diversity of causal agents
involved in allergic reactions also underlines the necessity to refer
these patients to centers with experience in drug allergy investigation to identify the responsible agent and provide recommendations for future anesthetic procedures.
The need for research in drug allergy has been strongly
advocated.32 However, the surveillance and analysis of adverse
drug reactions represent a statistical challenge because these reactions are rare, random, and mostly independent from the successive exposure of patients to a low-risk intervention.7 Because of
possible biases and underreporting, spontaneous reporting systems are usually considered inappropriate for the assessment of
adverse drug reaction rates.6,8,33 The capture-recapture method
has been used by epidemiologists to estimate the prevalence or incidence of diseases in human beings.10,11,34 It represents a helpful
tool for estimating frequency when several sources of information
are available and can be matched. Cases identified by each source
should be real cases and true matches, identified in the same population, in the same geographic area, during the same period.
These conditions have been fulfilled in the current study. Another
important condition is to be able to provide a precise estimate of
the number of patients exposed to the potentially offending agent.
This was achieved by accessing the database concerning anesthesia in France in 1996,20 considering that the number of anesthesias performed in France within the study period has remained
stable. This assumption can be regarded as acceptable because
the market shares of the various drugs used in anesthesia in France
within this period remained relatively stable.
In our series, a significant female predominance was observed
only in adults. This increased incidence of reaction remained
significant even when the frequency of reaction was adjusted for
the number of procedures performed. In addition, IgE-mediated
reactions to latex were observed at a younger age in children
compared with IgE-mediated reactions to NMBAs. Such sex
differences and changes in the sex ratio after puberty have been
previously reported in the literature for allergic reactions to
proteins in the case of asthma, atopic eczema, and food allergy.35
The hypothesis of a possible cross-sensitization with quaternary
ammonium ion–containing compounds such as cosmetics has
long been proposed to explain the increased incidence of immediate hypersensitivity reactions observed in women.36 However,
this hypothesis remains to be confirmed, and in their comprehensive study on the possible implication of household chemicals in
sensitization to NMBAs, Florvaag et al37 failed to identify a
possible responsible agent. Our results demonstrate that the
suspected influence of sex hormones on immediate-type IgE-mediated reactions is not limited to sensitization to proteins but also
involves allergy to low-molecular-weight compounds. Although
the mechanism of sensitization to small molecules might differ
in some cases from those to proteins,38 the rate of sensitization
to these drugs appears to be also influenced by sex hormones. Indeed, estrogens have been showed to act as immunomodulators39
able to skew the immune response toward a TH2 profile by acting
on dendritic as well as T cells and to enhance mast cell activation.39-41 Similarly, progesterone has been showed to potentiate
IgE formation in mice sensitized to house dust mite.42 In addition,
the higher incidence of non–immune-mediated hypersensitivity
reactions observed in our female patients suggests that estrogens
might also play a role in this increased rate of nonspecific effector
372 MERTES ET AL
cell activation and potentially in the enhanced synthesis and release of allergic mediators.43
A high incidence of allergic reactions to NMBAs is reported in
our study. Of all the drugs studied that elicit immediate allergic
reactions, these compounds demonstrate a number of intriguing
departures from the usually accepted explanations of the mechanisms underlying the allergic immune response to ‘‘small’’
molecules.
It has been generally assumed that conjugation of lowmolecular-weight compounds to a carrier protein was necessary
for cross-linking of mast cell–bound IgE and the subsequent
release of mediators of allergy. In 1983, Baldo and Fisher44 established that the quaternary ammonium ions and the tertiary amines
present in NMBAs were part of the epitopes involved in allergic
reactions to these drugs. Because the substituted ammonium
ions of NMBAs are responsible for both the neuromuscular blocking and allergenic properties and because there are at least 2 of
these groups separated by a distance of 1 to 1.45 nm, it was suggested that NMBAs elicit allergic mediator release by binding to
and bridging combining sites of adjacent cell-bound complementary IgE molecules via the ammonium groups. The divalency of
NMBAs explains the allergen-induced mediator release in a sensitized subject even in the absence of protein binding.
Another intriguing feature relates to the immunologic
dogma of previous exposure. In our series, as in previous
reports,12,18,45,46 a large proportion of subjects reacted on their
first exposure to an NMBA. Because the NMBAs’ epitopes involved in allergic reactions occur widely, not only in many drugs
but also in foods, cosmetics, disinfectants, and industrial materials, there has been speculation that the origin of allergic sensitization could be environmental agents or drugs containing an
ammonium ion or a tertiary amine. Thus, allergenic crossreactivity has been proposed to explain the lack of previous exposure seen in many of the patients with allergy. However, the theory
of environmental sensitization is not confirmed. Recently, Florvaag et al,47 taking advantage of the large difference in the incidence of allergic reactions to NMBAs, which is more than 6
times greater in Norway than Sweden, investigated the possible
sensitizing role of several environmental factors. They failed to
demonstrate any differences regarding the use of household
chemicals or other environmental factors. However, they reported
the presence of IgE antibodies to pholcodine, a morphinelike alkaloid with a quaternary ammonium ion, used in cough suppressants without restriction in Norway but not in Sweden, in 6% of
blood donors from Norway but in none of the Swedish donors.
In an international prevalence study, these authors provided additional support to the hypothesis of the possible sensitizing role of
pholcodine.48 However, the results suggest that other, yet unidentified substances may lead to IgE-sensitization toward NMBAs.
The study of possible risk factors for anaphylactic reactions
appears somewhat disappointing, because the relatively low
incidence and prevalence of anesthetic systemic reactions in the
general population will limit the ability to identify patients at risk.
Indeed, the majority of patients with a history of atopy, asthma,
family history, female sex, previous exposure, allergy to cosmetics, and nonanesthetic drugs will undergo uneventful anesthesia.
On the contrary, a previous anesthetic hypersensitivity reaction or
a history of an unexplained or undocumented anesthetic event are
significant risk factors and make investigation mandatory.
When an allergy to latex was found in our series, a large
proportion of reactors had a previous history of symptoms,
J ALLERGY CLIN IMMUNOL
AUGUST 2011
indicating a possible sensitization to latex. This demonstrates
that a standard preanesthetic questionnaire is not sufficiently
reliable to detect latex allergy because patients will not always
report signs indicating a possible sensitization when asked about
allergies. A specific inquiry about fruit or latex allergy should be
part of the routine preoperative interrogation. In addition, a
number of factors have been identified as predisposing to
anaphylaxis after exposure to latex. Children with spina bifida
or those who have undergone multiple operations are a major atrisk group for latex. This is confirmed by our results indicating a
large proportion of reactions involving latex in children. In
addition to detecting patients at risk, anaphylactic reactions to
latex potentially could be reduced by avoiding latex exposure in
patients with spina bifida from birth and avoiding exposure to
latex in operating rooms by provision of a latex-free environment
in children’s hospitals.49,50
This strategy of prevention by limiting patient exposure to
drugs considered high risk has also been shown to be effective in
the case of succinylcholine by limiting its use to patients requiring
emergency intubation and not using it as a prelude to a long-acting
NMBAs.51 These results and the high incidence of allergic reactions to NMBAs observed in women are a strong incentive for a
policy of risk reduction through avoidance of unnecessary exposure to potentially sensitizing compounds. Our results should be
considered when evaluating the relative risk of regional versus
general anesthesia in women as well as in children. This consideration can be extended to the indications for antimicrobial
prophylaxis, the use of which should be supported by an appropriate benefit-to-risk ratio estimate, as recently highlighted in the revised recommendation for prevention of infective endocarditis.52
Finally, considering the large number of drugs, diagnostic
reagents, devices containing latex or other sensitizing compounds, antiseptics, and blood products that are routinely used
in anesthesia, all of which may be involved in a reaction, a
systematic investigation of suspected hypersensitivity reactions is
mandatory. In view of the relative complexity of allergy investigation, an active policy should be promoted to identify patients
at risk, provide any necessary support such as expert advice to
anesthetists, and refer patients to centers with experience in drug
allergy investigation.
Clinical implications: The incidence of allergic reactions during
anesthesia is higher than previously estimated. A role for sex
hormones in the increase of anaphylaxis observed in women is
suggested.
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